Steroid intermediates

ABSTRACT

Total synthesis of steroids with substitution in the 2,3, 6, 11 or 17 positions comprising the step of cyclization of a compound having the formula ##STR1## or analogues thereof, where X represents ═O, ##STR2## or β-substituted ##STR3## Y represents ═O, β-oriented ##STR4## or β-orientated OH, R&#39; and R 2  may be the same or different and R&#39; represents alkyl or aryl and R 2  represents alkyl and Z represents ether or hindered ester to form the novel compounds ##STR5##

This invention relates to total steroid synthesis and to novelintermediates in said synthesis.

Steroid derivatives find widespread use pharmaceutically for example inthe control of inflammation, in the treatment of certain types ofcancer, and in hormone replacement therapy. The control of humanfertility by administration of steroids has also established for suchcompounds a position of commercial significance.

Many of these steroids are prepared by chemical transformation ofestrone. Estrone itself is manufactured commercially from compoundsextracted from plant sources for example diosgenin extracted fromMexican yams and stigmasterol extracted from soybeans. It is envisagedthat the availability of plant sources for the manufacture of estronemay decline. Although methods for total synthesis of estrone have beenproposed they seem commercially unattractive when compared to thesemi-synthetic methods using plant sources.

Steroids with unusual substitution patterns are less readily accessiblefrom estrone. Amongst the most important locations for unusualsubstitution are the 6 and 11 positions. The presence of a 6-substituenthas the effect of markedly increasing the physiological potency of sometherapeutically important steroids whilst the presence of an11-substituent is normally essential for the activity ofanit-inflammatory steroids. In addition steroids with an oxygen functionat the 3-position are pharmacologically much more interesting than 3unsubstituted compounds.

At present there is no direct chemical method available for theintroduction of functionality at the 11 position into the pre-existingsteroid skeleton. Microbiological processes are used for this purpose.

A commercially acceptable total synthesis of steroids with substitutionat the 11-position, and of steroids with substitution in both 6 and 11positions and with subsitution in the 3, 6, and 11 positions is,therefore, of considerable interest.

According to the invention there is provided a total synthesis ofsteroids with 11 position substitution and of steroids with 6 and 11position substitution characterized by the steps of cyclization of acompound having the formula ##STR6## where X represents ═0, ##STR7## orBeta orientated ##STR8## and R¹ and R² may be the same or different andR¹ represents alkyl and R² represents alkyl and Z represents alkoxy toform a compound having the formula ##STR9## Further, according to theinvention there is provided a total synthesis of steroids with 11position substitution and of steroids with 6 and 11 positionsubstitution characterized by the steps of cyclization of a compoundhaving the formula ##STR10## where X represents ═0, ##STR11## or Betaorientated ##STR12## and R¹ and R² may be the same or different and R¹represents alkyl and R² represents alkyl and Z represents alkoxy to forma compound having the formula ##STR13## Similarly, according to theinvention there is provided a total synthesis of steroids with 11position substitution and of steroids with 6 and 11 positionsubstitution and of steroids with 2, 6 and 11 position substitutioncharacterized by the steps of cyclization of a compound having theformula ##STR14## where Y represents ═0, ##STR15## β-orientated##STR16## or β-orientated OH and R¹ and R² may be the same or differentand R1 represents alkyl and R² represents alkyl to form a compoundhaving the formula ##STR17## According to the invention there is alsoprovided a total synthesis of steroids with 11 position substitution andof steroids with 6 and 11 position substitution and of steroids with 2,11, and 17 substitution characterized by the steps of cyclization of acompound having the formula ##STR18## where Y represents Beta orientatedOH or Beta orientated ##STR19## and R¹ and R² may be the same ordifferent and R¹ represents alkyl and R² represents alkyl to form acompound having the formula ##STR20## The products (2) and (4) of thecyclization process as defined above can, in a relatively few steps aswill be explained hereinafter, be converted into steroids with afunctional group at the 11-position, and to steroids with functionalgroups at both 6 and 11 positions and more particularly at the 3, 11,and 17 positions and at the 3, 6, 11, and 17 positions for examplehaving the formulae ##STR21## The products (2A) and (4A) of thecyclization process as defined above can also, in a relatively fewsteps, be converted into steroids with a functional group at the11-position, and to steroids with functional groups at both 6 and 11positions and more particularly at the 2, 11, and 17-positions forexample having the formulae ##STR22## Such steroids are ofpharmacological interest and moreover occupy a key position in schemesfor producing a wide variety of functionalized steroids by knownmethods. For example the functional groups of the 6 and 11 positionshave different reactivities which can be manipulated chemically forselective removal thereof and introduction if desired of additionalgroups at the 7, 9, 12, and/or 16 positions.

In addition to utilization as intermediates for the production of11-functionalized steroids and of 6, 11-difunctionalized steroids and of2,11-difunctionalized steroids the products (2) and (4) and (2A) and(4A) of the cyclization process are novel compounds of pharmacologicalinterest. Moreover the said products (2) and (4) and (2A) and (4A) canbe transformed into derivatives also having pharmacological properties.

The invention therefore, also provides novel compounds having theformulae ##STR23## where X and Y and Z are as previously defined.

The starting compounds (1) and (3) for the cyclization process can beprepared by any suitable route. We have found, and it is a preferredembodiment of the invention that compounds (1) and (3) can beconveniently prepared by the following synthesis.

Step 1-The anion of an allyl sulphone for example allyl phenyl sulphone##STR24## generated for example by treatment with n-butyl lithium in amixture of tetrahydrofuran and hexamethylphosphoric triamide, is treatedat -78° C. with an enone, for example 2-methylcyclopentenone.

The lithium enolate so formed is trapped by addition of the reactionmixture to an allylic halide, for example 3-methoxycinnamyl bromide toform the compound ##STR25## In variations of this procedure the lithiumenolate may be treated with triphenyltin chloride to give the tinenolate, which is then allowed to react with 4-methoxycinnamyl bromideto give compound (7), or the lithium enolate is treated withtrimethylsilyl chloride to give the trimethylsilyl enol ether, which isisolated and then allowed to react with4-methoxy-1-(1-hydroxypropenyl)benzene with zinc bromide catalysis togive the compound (7).

In this first step all the carbon atoms of the steroid skeleton areintroduced, and only one diastereoisomer of the product is obtained. Thereaction therefore proceeds stereoselectively to give the required transjunction about C-13-C-14, and, stereoselectively to give one epimer atC-8. Moreover by appropriate choice of starting materials functionalitycan be optionally introduced into the 2 position, or omitted from the 3position, and different alkyl groups can be introduced into the C-13position. For example the allylic halide can be one selected fromcompounds having the formula ##STR26## where R¹ and R² is H, and whereR¹ is H and R² is oxyalkyl, and where R¹ and R² is oxyalkyl, and X ishalide or sulphonate ester and the enone can be selected from compoundshaving the formula ##STR27## where R³ is alkyl.

The allyl sulphone that can be used includes compounds having theformula ##STR28## where R⁴ represents phenyl, p-tolyl, t-butyl,2-pyridyl, 2-(N-methylimidazolyl) or 2-thiazolinyl. In addition allylalkyl sulphones, particularly those in which the alkyl group is chiral,can also be used. The latter sulphones provide a useful basis forenantioselective preparation of analogues of compound 7. The advantagesof the use of an allyl sulphone in the above process can be appreciatedwhen the Step 1 described above is compared with an analogous process inwhich an allyl sulphide is employed. When an allyl sulphide is used anoxidation step is required before proceeding to reduction to produce the17β-alcohol (see subsequent Step 2). An equivalent oxidation step is notrequired when an allyl sulphone is used and potential difficultiesrelating to that selective oxidation are thus avoided. A most importantadvantage of the use of an allyl sulphone in this step is that only onediastereoisomer at C-8 is formed. Wtih an allyl sulphide a mixture ofdiastereoisomers at C-8 is obtained, which complicates isolation andcharacterization procedures.

Step 2-The product of step 1 is reduced preferably using a hydride forexample sodium borohydride in methanol and the 17β alcohol obtained.##STR29##

Step 3-The 17β alcohol produced in step 2 is converted into an ester bytreatment with for example trimethylacetyl chloride ##STR30## Acetylchloride can be used as an alternative to trimethylacetyl chloride, butthe acetate leads to lower yields in the subsequent steps 4 and 5.

Step 4-A mixture of the 9α,11α epoxide (10) and 9β,11β-epoxide (11) isproduced by oxidation of the product of Step 3 using for example aperoxyacid such as m-chloroperbenzoic acid in the presence of anhydrouspotassium fluoride in dichloromethane at room temperature ##STR31## Theratio of (10B) to (11B) formed when the reaction is performed at roomtemperature is ca. 2:1, whereas at 0° C. the ratio is 3.3:1. The mixtureof epoxides in the present process may decompose on chromatography onsilica and that mixture is, therefore, used in the next step withoutpurification.

The compounds (10) and (11) may be converted into the same steroids with`correct` stereochemistry so that the absence of high stereoselectivityin step 4 is not serious. Compound (11) can be used to obtain steroidsof unnatural configuration at position 9.

Step 5-The mixture of epoxides from Step 4 is reacted with an alkyl tinhydride which would not reduce the epoxy group for exampletri-n-butyltin hydride to yield the starting materials for thecyclization process ##STR32## For the 9α,11α epoxide (1) the cyclizationprocess of the invention proceeds to give compound (2) at an appreciablerate under the reaction conditions of Step 5. The cyclization may befurther promoted by a variety of proton acids or Lewis acids for exampletrifluoroacetic acids or tin(IV) chloride or zinc bromide, preferably atreduced temperature for example at from -78° C. to 0° C. For the 9β,11βepoxide (3) the cyclization process of the invention to give (4) can bepromoted by a variety of Lewis acids for example tin(IV) chloride orzinc bromide. The process is preferably carried out at reducedtemperature for example at from -78° C. to 0° C.

The starting compounds (1A) and (3A) for the cyclization process canalso be prepared by any suitable route. We have found, and it is apreferred embodiment of the invention that compounds (1A) and (3A) canbe conveniently prepared from cinnamyl bromide by procedures analogousto those in the foregoing steps 1-5, which provide in sequence thecompounds (7A), (8A), (9A), and (10A) and (11A), and ultimately (1A) and(3A). For the conversion of (9A) into the epoxides (10A) and (11A)metachloroperbenzoic acid was used. It was not necessary to addpotassium fluoride. The epoxides (10A) and (11A) werechromatographically identical and could not be separated, but they didnot decompose on chromatography. ##STR33## As previously mentioned thenovel compounds produced by the cyclization process of the invention canbe converted into 11-functionalized steroids and 6,11- functionalizedsteroids. Preferred synthesis for those conversions are as follows. (Thestep numbers that follow assume that Step 6 in a complete synthesis tothe steroids would be the cyclization process of the invention).

FIRST SYNTHESIS

Step 7-The product (2) (X=17B-OAc) (Z=OMe) of the cyclization process ishydrolysed to the 3-methoxy 11α,17β-diol ##STR34##

Step 8-The diol from Step 7 is esterified to give the3-methoxy-11α,17β-di(trimethylacetate) ##STR35## The methoxy diester(13) is also obtained by esterification with trimethylacetyl chloride ofthe product

(2) X=17β-trimethylacetoxy) of the cyclization process.

Step 9-The product from Step 8 is converted into the corresponding6-alcohol by hydroboration followed by oxidation ##STR36##

Step 10-The 6-hydroxy compound formed in Step 9 is further oxidised togive the acid ##STR37##

Step 11-The acid from Step 10 is converted into the acid chloride andthen treated with aluminium chloride to produce the3-methoxy-11α,17β-di(trimethylacetoxy)-6-keto steroid ##STR38##

Step 12-Hydrolysis of the fully cyclized product from Step 11 furnishesthe

3-methoxy-11α,17β-dihydorxy-6-keto-estra-1,3,5(10)-triene ##STR39##

SECOND SYNTHESIS

Step 7a-The product (4) (X=OAc) (Z=Ome) of the cyclization process isoxidised to the corresponding 11-ketone ##STR40##

Step 8a-Under basic conditions the ketone obtained in Step 7a isconverted into its isomer at C-9. ##STR41##

Step 9a-The ketone obtained in Step 8a is reduced preferably using ahydride for example sodium borohydride and the 11β-alcohol obtained,(together with a small proportion of the 11α alcohol) ##STR42##

Step 10a-The 11β-alcohol obtained in Step 9a is esterified by treatmentfor example with acetyl chloride to give the 3-methoxy-11β,17β-diacetoxyderivative ##STR43##

Step 11a-The methoxy diacetate from Step 10a is converted into thecorresponding 6-alcohol by hydroboration followed by oxidation ##STR44##

Step 12a-Oxidation of the 6-alcohol from Step 11a gives thecorresponding acid ##STR45##

Step 13a-The acid from Step 12a is converted into the acid chloride andthen treated with aluminium chloride to produce the3-methoxy-11β,17β-diacetoxy-6-keto steroid ##STR46##

Step 14a-Hydrolysis of the fully cyclized product from Step 13afurnishes the

3-methoxy-11β,17β-dihydroxy-6-keto-estra-1,3,5(10)-triene ##STR47##

THIRD SYNTHESIS

3-Methoxy-11β,17β-diacetoxy-6-hydroxy-5,6-seco-estra-1,3,5(10)-triene(21) is obtained by Step 11a as before

Step 12b-The 6-hydroxy compound from Step 11a is converted into thecorresponding chloride by treatment for example with triphenyl phosphinein carbon tetrachloride ##STR48##

Step 13b-The chloride from Step 12b is treated with aluminium chlorideto give the 3-methoxy-11β,17β-diacetoxy steroid ##STR49##

Step 14b-Hydrolysis of the fully cyclized product from Step 13bfurnishes the 3-methoxy-11β,17β-dihydroxy-estra-1,3,5(10)-triene##STR50##

FOURTH SYNTHESIS

3-Methoxy-11α,17β-di(trimethylacetoxy)-6-hydroxy-5,6-seco-estra-1,3,5(10)-triene(14) is obtained by step 9 as before.

Step 10c-The 6-hydroxy compound from Step 9 is converted into thecorresponding methanesulphonate by treatment with methanesulphonylchloride and triethylamine, and the crude product is treated withaluminium chloride in dichloromethane to give the3-methoxy-11α,17β-di(trimethylacetoxy) steroid ##STR51##

Step 11c-The fully cyclized product from Step 10c is treated withlithium aluminium hydride to give

3-methoxy-11α,17β-dihydroxy-estra-1,3,5(10)-triene ##STR52##

FIFTH SYNTHESIS

Methods analogous to the foregoing first synthesis are used to convertthe product of cyclization (2A) (Y=17β-trimethylacetoxy) into11α,17β-6-keto-estra-1,3,5(10)-triene (5A) via the intermediates (13A),(14A), (15A), and (16A). ##STR53##

SIXTH SYNTHESIS

The hydroxy di(trimethylacetate) (14A) is obtained by the first twosteps of the foregoing fifth synthesis. This is converted by stepsanalogous to the fourth synthesis via the diester (26A) into11α,17β-dihydroxy-estra-1,3,5(10)-triene (6C). ##STR54##

SEVENTH SYNTHESIS

11α,17β-Di(trimethylacetoxy)-estra-1,3,5(10)-triene (26A) was obtainedas before (see sixth synthesis).

Step 11d-The diester (26A) is treated with acetyl chloride and aluminiumchloride to give the corresponding 2-acetyl compound ##STR55##

Step 12d-The product of Step 11d is treated with metachloroperbenzoicacid to give the 2-acetoxy compound ##STR56##

Step 13d-The triester (28) is treated with lithium aluminium hydride togive 2,11α,17β-trihydroxyestra-1,3,5(10)-triene ##STR57## In theforegoing description, the production of compounds 1, 2, 3, and 4 andthe production of compounds derived therefrom has been exemplified bycompounds with a methoxy group in the 3-position. It is to be understoodthat the substitution in the 3-position may be a different ether or ahindered ester group for example RO-- where R is alkyl, and ArCH₂ O-- orAr₂ CHO-- where Ar is phenyl or tolyl or 4-methoxyphenyl or other alkyl-or alkoxy-substituted phenyl residues, and RC(O)O-- where R is t-butylor 1-adamantyl or 2,6-dialkylphenyl or 2,4,6-trialkylphenyl.

EXPERIMENTAL

Melting points were determined with a Kofler block apparatus. Infra-redspectra were determined with a Perkin-Elmer 157G spectrophotometer, andmass spectra with a Kratos MS25 or MS80 spectrometer. Proton n.m.r.spectra refer to deuteriochloroform solutions with tetramethylsilane asinternal standard: they were determined at 220 MHz (unless otherwiseindicated), with a Perkin-Elmer R34 spectrometer, and spectra at 250 and400 MHz were determined respectively with Bruker AM250 and WH400instruments. Column chromatography was performed with Merck 7736 60Hsilica gel. Ether refers to diethyl ether, and light petroleum to thefraction boiling between 40° and 60° C. After extraction procedures,organic solvents (usually ether) were dried over magnesium sulphate. Inthe nomenclature of the following compounds steroid numbering is used.

3-Methoxy-8ξ-phenylsulphonyl-8,9-seco-5,6-secoestra-1,3,5(10),6,9(11)-pentaene-17-one(7).

Method 1.

A solution of allyl phenyl sulphone (0.379 g, 2.1 mmol) in drytetrahydrofuran (THF) (6ml) and hexamethylphosphoric acid triamide(HMPA) (0.8 ml) was treated with n-butyl-lithium (0.91 ml of a 2.3Msolution in hexane, 2.1 mmol) at -78° C. under argon. After 15 min thedeep orange solution was treated with 2-methylcyclopentenone (2) (0.2 g,2.1 mmol), the mixture was stirred for a further 15 min, and thentransferred by cannula dropwise to a solution of 4-methoxycinnamylbromide (1.2 g, 5.3 mmol) in dry THF (6 ml) at -20° C. After a further30 min at -20° C. a solution of thiourea (0.8 g, 10.5 mmol) indimethylformamide (10 ml) was added, and the mixture was heated at 100°C. for 10 min, and the solvent was then removed by evaporation underreduced pressure. The residue was treated with water (10 ml) andextracted with ether (3×20 ml). After the ethereal extract was washedwith water, dried, and evaporated, the residue was chromatographed onsilica (10 g) and eluted with ether-light petroleum (2:3) to give theproduct (7) (660 mg, 75%), m.p. 135-6° C. (from ethanol), ν_(max) 1735(CO), 1140 cm⁻¹ (SO₂), δ (250 MHz) 7.7-7.4 (7 H, m, aromatic protons),6.87 (2 H, d, J 8 Hz, 2- and 4-protons), 6.49 (1 H, d, J 16 Hz, ArCH),6.04 (1 H, dt, J 16 and 8 Hz, ArC═CH), 5.87 (1H, dt, 17 and 10 Hz,7-proton), 5.23 (1 H, dd, H 10 and 1 Hz, cis 6-proton), 4.81 (1 H, dd, J17 and 1 Hz, trans 6-proton), 3.83 (3 H, s, OCH₃), 3.80 (1 H, dd, J 10and 2 Hz, 8-proton), 3.22 (1 H, ddd, J 10, 5.5, and 2 Hz, 14-proton),2.5-1.9 (6 H, m), 0.91 (3 H, s, 18--CH₃); (Found: C, 70.5; H, 6.5; S,7.5; M⁺ 424.1712. C₂₅ H₂₈ O₄ S requires C, 70.8; H, 6.6; S, 7.6%; M424.1708).

Method 2.

A solution of allyl phenyl sulphone (0.632 g, 3.5 mmol) in drytetrahydrofuran (THF) (10 ml) and hexamethylphosphoric acid triamide(HMPA) (1.33 ml) was treated with n-butyl-lithium (2.3 ml of a 1.5Msolution in hexane, 3.5 mmol) at -78° C. under argon. After 15 min thedeep orange solution was treated with 2-methylcyclopentenone (2) (0.333g, 3.5 mmol), the mixture was stirred for a further 15 min, and thentreated with triphenyltin chloride (1.47 g, 382 mmol). After beingstirred for 30 min, the mixture was treated with a solution of4-methoxycinnamyl bromide (2.36 g, 10.4 mmol) in dry THF (12 ml), andallowed to warm to room temperature. After a further three hours a 10%solution of potassium fluoride was added, the mixture was stirred for 15min, filtered, and the filtrate evaporated to dryness. The residue wasextracted with ether, and the ethereal extract was processed in the sameway as described in Method 1 to give the product (7) (617 mg, 42%).

Method 3.

A solution of allyl phenyl sulphone (2.767 g) in dry tetrahydrofuran(THF) (29 ml) and hexamethylphosphoric acid triamide (HMPA) (5.4 ml) wastreated with n-butyl-lithium (11.97 ml of a 1.5M solution in hexane) at-78° C. under argon. After 15 min the deep orange solution was treatedwith 2-methylcyclopentenone (2) (1.459 g), the mixture was stirred for afurther 15 min, and then treated with chlorotrimethylsilane (19.1 ml).After evaporation of the solvent under reduced pressure the residue wasextracted with petroleum ether containing a few drops of triethylamine,and the extract washed rapidly with water and dried (MgSO4). Evaporationof the solvent gave the crude enol silyl ether (3.90 g, 81%), a portionof which (200 mg, 0.63 mmol) was dissolved in dry acetonitrile (0.5 ml)and treated with anhydrous zinc bromide (28 mg, 0.12 mmol). After 15 mina solution of 4-methoxy-1-(1-hydroxyprop-3-enyl)benzene (103 mg, 0.63mmol) in dry acetonitrile (0.5 ml) was added, and the resulting solutionwas kept at 40° C. for 40 hours. The solution was cooled, water (5 ml)was added, and the mixture was extracted with dichloromethane. Theextract was dried and evaporated to give a residue which waschromatographed on silica eluted with ether-light petroluem (3:10) togive the product (7) (119 mg, 45%)

8ξ-phenylsulphonyl-8,9-seco-5,6-secoestra-1,3,5(10),6,9(11)-pentaene-17-one(7A).

This was prepared by Method 1 (outlined above) from cinnamyl bromide(4.44 g) and 2-methylcyclopentenone (1.45 g) which gave the product (7A)(3.887 g, 64%), m.p. 79-81° C., ν_(max) 1740 (CO), δ (250 MHz) 7.9-7.2(10 H, m, aromatic protons), 6.56 (1 H, d, J 16 Hz, 9-proton), 6.20 (1H, dt, J 16 and 8 Hz, 11-proton), 5.87 (1 H, dt, 16.5 and 10 Hz,7-proton), 5.23 (1 H, dd, H 10 and 1 Hz, cis 6-proton), 4.80 (1 H, dd, J16.5 and 1 Hz, trans 6-proton), 3.80 (1 H, dd, J 10.5 and 2 Hz,8-proton), 3.22 (1 H, ddd, J 10.5, 5.5, and 2 Hz, 14-proton), 2.5-1.9 (6H, m), 0.92 (3 H, s, 18-CH₃);

(Found: C, 72.85; H, 6.95; S, 8.4; M⁺ 394. C₂₄ H₂₆ O₃ S requires C,73.1; H, 6.9; S, 8.1%; M 394).

3-Methoxy-8ξ-phenylsulphonyl-8,9-seco-5,6-secoestra-1,3,5(10),6,9(11)-pentaene-17-ethyleneketal (7E).

A solution of the keto sulphone (7) (197 mg, 0.46 mmol) andp-toluenesulphonic acid (10 mg) in a mixture of benzene (30 ml) andethane-1,2-diol (86 mg, 1.4 mmole) was refluxed for 6 hours, withseparation of water by means of a Dean-Stark apparatus. The cooledsolution was passed through a column of alumina (2 g) and evaporated togive the product (7E) (133 mg, 61%) as an oil, ν_(max) 1150 cm⁻¹ (SO₂),δ 7.63-7.28 (7 H, m, aromatic protons), 6.87 (2 H, d, J 8.5 Hz, 2- and4-protons), 6.44 (1 H, d, J 15.5 Hz, 9-protons), 6.17 (1 H, ddd, J 15.5,8, and 6.5 Hz, 11-proton), 5.90 (1 H, dt, J 17 and 10 Hz, 7-proton),5.19 (1 H, dd, J 10 and 1 Hz, cis-6-proton), 4.71 (1 H, dd, J 17 and 1Hz, trans-6-proton), 3.98-3.80 (5 H, m, OCH₂ CH₂ O and 8-proton), 3.83(3 H, s, OCH₃), 3.13 (1 H, t, J 10 Hz, 14-proton), 2.44-1.77 (6 H, m),0.94 (3 H, s, 18-CH₃), (Found: M⁺ 468.1943. C₂₇ H₃₂ O₅ S requires468.1970).

3-Methoxy-8ξ-phenylsulphonyl-8,9-seco-5,6-secoestra-1,3,5(10),6,9(11)-pentaene-17β-ol(8).

Sodium borohydride (1.37 g, 36 mmol) was added to a solution of theoxo-sulphone (7) (3.05 g, 7.2 mmol) in dry ethanol (130 ml) at 20° C.After 90 min dilute hydrochloric acid was added, the solvent wasevaporated under reduced pressure, and the residue was partitionedbetween ether and water. The ethereal extract was washed with dilutehydrochloric acid and water, dried and evaporated to give a residuewhich was chromatographed on silica (30 g). Elution with ether-lightpetroleum (1:1) gave the product (8) (2.97 g, 97%), m.p. 45°-6° C.,ν_(max) 3520 (OH) and 1140 cm² (SO₂), δ (250 MHz) 7.52-7.3 (7 H, m,aromatic protons), 6.86 (2 H, d, J 8 Hz, OCH₃), 6.47 (1 H, d, J 15 Hz,9-proton), 6.41 (1 H, dt, J 15 and 8 Hz, 11-proton), 5.88 (1 H, dt, J16.5 and 10 Hz, 7-proton), 5.23 (1 H, dd, H 10 and 1 Hz, cis 6-proton),4.81 (1 H, dd, J 16.5 and 1 Hz, trans 6-proton), 3.90 (1 H, t, J 8 Hz,17-proton), 3.82 (3 H, s, OCH₃), 3.81 (1 H, dd, J 10 and 1.5 Hz,8-proton), 2.70 (1 H, dt, J 10 and 1.5 Hz, 14-proton), 2.28 (2 H, ddd, J8, 5, and 1 Hz, 12-protons), 2.06 (1 H, m, 16-proton), 1.95 (2 H, m),1.70 (1 H, br s, OH), 1.52 (1 H, m, 16-proton), 0.79 (3 H, s, 18-CH₃);

(Found: C, 70.4; H, 6.9; S, 7.7%; M⁺ 426.1871. C₂₅ H₃₀ O₄ S requires C,70.4; H, 7.0; S, 7.5%; M 426.1864).

3-Methoxy-8ξ-phenylsulphonyl-8,9-seco-5,6-secoestra-1,3,5(10),6,9(11)-pentaene-17β-ylacetate (9).

A solution of the hydroxy-sulphone (8) (1.52 g, 3.57 mmol) in drybenzene (20 ml) was treated with dry silver cyanide (956 mg, 7.14 mmol)and acetyl chloride (1.3 ml, 18.2 mmol) at room temperature. After 16 hether (20 ml) was added, the solution was filtered throughHyflosupercel, and the filtrate evaporated under reduced pressure.Chromatography of the residue on silica (20 g) eluted with ether-lightpetroleum (1:1) gave the product (9) (1.60 g, 96%), m.p. 118°-119° C.(from ether-light petroleum), ν_(max) 1730 cm⁻¹ (CO), δ 7.72-7.26 (7 H,m, aromatic protons), 6.86 (2 H, d, J 8 Hz, 2- and 4-protons), 6.40 (2H, d, J 16 Hz, 9-proton), 6.11 (1 H, dt, J 16 and 8 Hz, 11-proton), 5.89(1 H, dt, J 17 and 10 Hz, 7-proton), 5.27 (1 H, dd, J 10 and 1 Hz, cis6-proton), 4.87 (1 H, dd, J 8 and 6 Hz, 17-proton), 4.86 (1 H, dd, J 17and 1 Hz, trans 6-proton), 3.82 (3 H, s, OCH₃), 3.80 (1 H, dd, J 10 and2 Hz, 8-proton), 2.69 (1 H, ddd, J 10, 8, and 2 Hz, 14-proton),2.26-1.87 (4 H, m, 15- and 16-protons), 1.98 (3 H, s, COCH₃), 0.84 (3 H,s, 18-CH₃);

(Found: C, 69.3; H, 6.8; S, 6.7%; M⁺ 468.1967. C₂₇ H₃₂ O₅ S requires C,69.2; H, 6.8; S, 6.8%; M 468.1970).

8ξ-Phenylsulphonyl-8,9-seco-5,6-secoestra-1,3,5(10),6,9(11)-pentaene-17.beta.-yltrimethylacetate (9A).

Treatment of the alcohol (8A) (3.50 g) with trimethylacetyl chloride andsilver cyanide in the above manner gave the ester (9A) (3.35 g, 79%), asa waxy solid, ν_(max) 1720 (C═O) and 1145 cm⁻¹ (SO₂), δ 7.72-7.18 (10 H,m, aromatic protons), 6.44 (1 H, d, J 16 Hz, 9-proton), 6.25 (1 H, dt, J16 and 7 Hz, 11-proton), 5.88 (1 H, dt, J 17 and 10 Hz, 7-proton), 5.25(1 H, dd, J 10 and 1 Hz, cis 6-proton), 4.83 (1 H, dd, J 17 and 1 Hz,trans 6-proton), 4.85 (1 H, dt, J 8 and 1.5 Hz, 17-proton), 3.79 (1 H,dd, J 10 and 1.5 Hz, 8-proton), 2.73 (1 H, dt, J 10 and 1.5 Hz,14-proton), 2.29-1.35 (6 H, m), 1.13 (9 H, s, OBu^(t)), 0.86 (3 H, s,18-CH₃),

(Found: C, 72.6; H, 7.7; S, 6.9; M⁺ 480. C₂₉ H₃₆ O₄ S requires C, 72.5;H, 7.55; S, 6.7%; M 480).

3-Methoxy-8ξ-phenylsulphonyl-8,9-seco-5,6-secoestra-1,3,5(10),6,9(11)-pentaene-17β-yltrimethylacetate (9B).

A solution of the hydroxy-sulphone (8) (201 mg, 0.94 mmol) in drybenzene (2 ml) was treated with dry silver cyanide (130 mg, 0.94 mmol)and trimethylacetyl chloride (74 mg, 0.61 mmol) at room temperature.After 19 h ether (2 ml) was added, the solution was filtered throughHyflosupercel, and the filtrate evaporated under reduced pressure.Chromatography of the residue on alumina eluted with ethyl acetate-lightpetroleum (1:10) gave the product (9B) (162 mg, 61%), m.p. 115°-116° C.(from ether-light petroleum), ν_(max) 1730 cm⁻¹ (CO), δ 7.72-7.27 (7 H,m, aromatic protons), 6.86 (2 H, d, J 8 Hz, 2- and 4-protons), 6.39 (1H, d, J 15.5 Hz, 9-proton), 6.10 (1 H, dt, J 15.5 and 8 Hz, 11-proton),5.89 (1 H, dt, J 17 and 10 Hz, 7-proton), 5.26 (1 H, dd, J 10 and 1 Hz,cis 6-proton), 4.86 (1 H, dd, J 17 and 1 Hz, trans 6-proton), 4.83 (1 H,dd, J 8 and 6.5 Hz, 17-proton), 3.82 (3 H, s, OCH₃), 3.81 (1 H, dd, J 11and 2 Hz, 8-proton), 2.70 (1 H, dt, J 11 and 2 Hz, 14-proton), 2.25-1.40(6 H, m) 1.37 (3 H, s, 18-CH₃), 1.15 (9 H, s, OBu^(t));

(Found: M+ 510.2467. C₃₀ H₃₈ O₅ S requires M 510.2439).

9α,11α-Epoxy-3-methoxy-8ξ-phenylsulphonyl-8,9-seco-5,6-secoestra-1,3,5(10),6-tetraene-17β-ylacetate (10) and its 9β, 11β-isomer (11).

Dry potassium fluoride (70 mg, 1.2 mmol) was added to a stirred solutionof m-chloroperbenzoic acid (191 mg, 1.11 mmol) in dry dichloromethane(25 ml). After stirring at room temperature for 15 min, a solution ofthe acetoxy-sulphone (9) (173 mg, 0.37 mmol) in dry dichloromethane (2ml) was added, and the mixture was stirred for a further 24 h at roomtemperature. The mixture was filtered, and the filtrate was treated withmore potassium fluoride (70 mg, 1.2 mmol) for 10 min, with vigorousstirring. After a further filtration, the filtrate was evaporated underreduced pressure to give a mixture of the crude products (10) and (11),(180 mg, quantitative), ν_(max) 1730 cm⁻¹ (CO), δ 7.82-7.12 (7 H, m,aromatic protons), 6.85 (2 H, d, J 8 Hz, 2- and 4-protons), 5.85 (1 H,m, 7 -proton), 5.25 (1 H, d, J 10 Hz, cis 6-proton), 4.89 (1 H, d, J 17Hz, trans 6-proton), 4.91 (1 H, m, 17-proton), 3.78 (3 H, s, OCH₃), 3.70(1 H, m, 8-proton), 3.54 and 3.50 (1 H, 2 s, 9-proton), 2.96 (1 H, m,11-proton), 2.64 (1 H, d, J 11 Hz, 14-proton), 2.2 (1 H, m), 2.04-1.4 (5H, m), 1.90 and 1.51 (3 H, 2 s, COCH₃), 0.90 and 0.87 (3 H, 2 s,18--CH₃),

(Found: M⁺ 482. C₂₇ H₃₂ O₆ requires M 482), in the ratio 1:1 accordingto n.m.r. spectroscopy. The mixture could not be purified bychromatography, since the compounds decomposed on contact with silicaand alumina. It was therefore used in the crude state for the next step.

3-Methoxy-9α,11α-epoxy-8ξ-phenylsulphonyl-8,9-seco-5,6-secoestra-1,3,5(10),6-tetraene-17β-yltrimethylacetate (10B), and its 9β,11β-isomer (11B).

Oxidation of the olefin (9B) (850 mg) in the above manner gave a mixtureof the epoxides (10B) and (11B) (880 mg, quantitative), in the ratio2:1, δ 7.81-7.14 (7 H, m, aromatic protons), 6.87 (2 H, d, J 8 Hz, 2-and 4-protons), 5.88 (1 H, two dt, J 17 and 10 Hz, 7-proton), 5.27 (1 H,two dd, J 10 and 1 Hz, cis-6-proton), 4.89 (1 H, dd, J 17 and 1 Hz,trans-6-proton), 4.82 (1 H, m, 17-proton), 3.80 (3 H, s, OCH₃), 3.72 (1H, m, 8-proton), 3.53 (1 H, two d, J 2 Hz, 9-proton), 3.00 (1 H, m),1.14 and 1.13 (9 H, two s, OBu^(t)), 0.97 and 0.95 (3 H, two s, 18-CH₃).When the oxidation was carried out at 0° C. for two days, the epoxideswere obtained in the ratio 3.3:1. The crude epoxides were used directlyfor the next step, because they decomposed on chromatography.

3-Methoxy-9α,11α-epoxy-8ξ-phenylsulphonyl-8,9-seco-5,6-secoestra-1,3,5(10),6-tetraene-17-one(10C), and its 9β,11β-isomer (11C).

Oxidation of the unsaturated keto sulphone (7) (192 mg) in the abovemanner gave a mixture (203 mg, quantitative) of the epoxides (10C) and(11C), in the ratio 1:1 according to its n.m.r. characteristics, δ7.84-7.15 (7 H, m, aromatic protons), 6.88 (2 H, d, J 8 Hz, 2- and4-protons), 5.89 (1 H, two dt, J 17 and 10 Hz, 7-proton), 5.25 (1 H, twodd, J 10 and 1 Hz, cis-6-proton), 4.86 (1 H, two d, J 17 Hz,trans-6-proton), 3.88-3.79 (1 H, m, 8-proton), 3.80 (3 H, s, OCH₃), 3.71and 3.55 (1 H, two d, J 4 Hz, 9-proton), 3.29-3.05 (2 H, m, 11- and14-protons), 2.51-1.87 (5 H, m), 0.96 and 0.94 (3 H, two s, 18-CH₃),

(Found: M⁺ 440.1663. C₂₅ H₂₈ O₅ S requires M 440.1657).

3-Methoxy-9α,11α-epoxy-8ξ-phenylsulphonyl-8,9-seco-5,6-secoestra-1,3,5(10),6-tetraene-17-ethyleneketal (10E), and its 9β,11β-isomer (11E).

Oxidation of the unsaturated keto sulphone acetal (7E) (110 mg) in theabove manner gave a mixture (121 mg, quantitative) of the epoxides (10E)and (11E) in the ratio 1:1 according to its n.m.r. characteristics,ν_(max) 1140 cm⁻¹ (SO₂), δ 7.83-7.13 (7 H, m, aromatic protons), 6.86 (2H, d, J 8 Hz, 2- and 4-protons), 5.92 (1 H, m, 7-proton), 5.23 (1 H, d,J 10 Hz, cis-6-proton), 4.85 (1 H, two dd, J 17 Hz, trans-6-proton),4.02-3.67 (5 H, m, OCH₂ CH₂ O and 8-proton), 3.78 (3 H, s, OCH₃), 3.56and 3.53 (1 H, two s, 9-proton), 3.22-2.94 (2 H, m, 11- and 14-proton),2.42-1.49 (7 H, m), 1.01 and 0.93 (3 H, two s, 18-CH₃),

(Found: M⁺ 484.1936. C₂₇ H₃₂ O₆ S requires M 484.1919.)

8ξ-Phenylsulphonyl-9α,11α-epoxy-8,9-seco-5,6-secoestra-1,3,5(10)-tetraaene-17β-yltrimethylacetate (10A) and its 9β,11β-isomer (11A).

A solution of the olefin (9A) (210 mg, 0.42 mmol) and m-chloroperbenzoicacid (79 mg, 0.46 mmol) in dry methylene chloride (2 ml) was stirred at0° C. for 5 hours. The mixture was diluted with dichloromethane, washedwith sodium bicarbonate and water, dried and evaporated to give aresidue which was chromatographed on silica. Elution with ether-lightpetroleum (3:10) gave the epoxides (10A) and (11A) (185 mg, 89%) as aninseparable mixture, ν_(max) 1720 (C═O) and 1145 cm⁻¹ (SO₂), δ (250 MHz)7.84-7.31 (10 H, m, aromatic protons), 5.90 (1 H, two dt, J 17 and 10Hz, 7-proton), 5.28 (1 H, two dd, J 10 and 1 Hz, cis-6-proton), 4.90 (1H, two dd, J 17 and 1 Hz, trans 6-proton), 4.89 (1 H, two t, J 7.5 Hz,17-proton), 3.80 (1 H, two dd, J 10 amd 1.5 Hz, 8-proton), 3.58 (1 H,two d, J 2 Hz, 9-proton), 2.98 (1 H, two dt, J 6 and 2 Hz, 11-proton),2.69 (1 H, two t, J 10 Hz, 14-proton), 2.35-1.40 (m, aliphatic protons),1.21 and 1.19 (9 H, two singlets, OBu^(t)), 0.97 and 0.91 (3 H, twosinglets, ratio 1.67:1, 18-CH₃).

(Found: C, 70.0; H, 7.45; S, 6.5. C₂₉ H₃₆ O₅ S requires C, 70.1, H, 7.3;S, 6.45%.). M+ (ammonia chemical ionization 514. C₂₉ H₃₆ O₅ S.NH₃requires 514.

3-Methoxy-6-Tri-n-butylstannyl-9α,11α-epoxy-17β-acetoxy-8,9-seco-5,6-secoestra-1,3,5(10),7-tetraene(1), and its 9β,11β-isomer (3).

2,2-Azobis-2-methylpropionitrile (50 mg, 0.3 mmol) was added to aboiling solution of tri-n-butyltin hydride (7.4 g, 25 mmol) and theallyl sulphones (10) and (11) (4.9 g, 10 mmol) in dry benzene (60 ml)under argon. After 10 min, the solution was cooled, and the solvent wasevaporated under reduced pressure to give a crude mixture of theproducts (1) and (3) (12 g), together with organotin byproducts and someof the cyclized product (2). The crude mixture was used directly for thenext step, because it underwent extensive decomposition onchromatography.

3-Methoxy-6-Tri-n-butylstannyl-9α,11α-epoxy-17β-trimethylacetoxy-8,9-seco-5,6-secoestra-1,3,5(10),7-tetraene(1B), and its 9β,11β-isomer (3B).

Treatment of a mixture of the epoxy sulphones (10B) and (11B) (880 mg)in the above manner gave a crude mixture of the epoxy allyl stannanes(1B) and (3B) (2 g) which was used directly for the next step.

3-Methoxy-11α-hydroxy-5,6-seco-9α-estra-1,3,5(10),6-tetraene 17β-ylacetate (2) and3-methoxy-11β-hydroxy-5,6-seco-9β-estra-1,3,5(10),6-tetraene-17.beta.-ylacetate (4).

A solution of the crude allyl stannanes (1) and (3) (12 g) from theprevious step was treated with dry zinc bromide (3 g, 13.3 mmol) at -78°C. under argon. After being allowed to warm to room temperatureovernight the mixture was treated with dilute hydrochloric acid andextracted with ether. The ethereal extract was washed with dilutehydrochloric acid, then with water, dried, and evaporated, to give aresidue which was chromatograpahed on silica (100 g), eluted first withether-light petroleum (3:7) and then with ether-light petroleum (1:1) togive first, the oily3-methoxy-11β-hydroxy-5,6-seco-9β-estra-1,3,5(10),6-tetraene-17b-ylacetate (4), (1.0 g, ca. 38% from (9), contaminated by some organotinbyproduct), ν_(max) 3450 (OH) and 1730 cm⁻¹ (CO), δ (250 MHz) 7.09 (2 H,d, J 8.5 Hz, 1- and 5-protons), 6.81 (2 H, d, J 8.5 Hz, 2- and4-protons), 5.05 (2 H, m, vinylic protons), 4.82 (2 H, m, vinylicproton, and 17-proton), 4.24 (1 H, dt, J 4.5 and 2.5 Hz, 11-proton),3.80 (3 H, s, OCH₃), 3.08 (1 H, ddd, J 5, 2, and 1 Hz, 9-proton), 2.80(1 H, m), 2.10 (3 H, s, COCH₃), 2.10-2.00 (3 H, m), 1.71-1.33 (5 H, m),1.15 (3 H, s, 18-CH₃);

(Found: M⁺ 344.1969. C₂₁ H₂₈ O₄ requires M 344.1987), and then

3-methoxy-11α-hydroxy-5,6-seco-9α-estra-1,3,5(10),6-tetraene-17b-ylacetate (2) (1.1 g, 63% from (9)) as an oil, ν_(max) 3450 (OH) and 1730cm⁻¹ (CO), δ 7.09 (2 H, d, J 8 Hz, 1- and 5-protons), 6.85 (2 H, d, J 8Hz, 2- and 4-protons), 5.31 (1 H, ddd, J 16.5, 10, and 8 Hz, 7-proton),4.74 (1 H, dd, J 10 and 2 Hz, cis-6-proton), 4.72 (1 H, t, J 8 Hz,17-proton), 4.67 (1 H, dd, J 16.5 and 2 Hz, trans 6-proton), 3.94 (1 H,ddd, J 11.5, 10, 5, and 2.5 Hz, 11-proton), 3.79 (3 H, s, OCH₃),2.45-2.16 (4 H, m), 2.04 (3 H, s, COCH₃), 1.53-1.22 (6 H, m), 1.00 (3 H,s, 18-CH₃);

(Found: M⁺ 344.2000. C₂₁ H₂₈ O₄ requires M 344.1987).

3-Methoxy-11α-hydroxy-5,6-seco-9α-estra-1,3,5(10),6-tetraene-17β-yltrimethylacetate (2B) and3-methoxy-11β-hydroxy-5,6-seco-9β-estra-1,3,5(10),6-tetraene-17.beta.-yltrimethylacetate (4B).

Treatment of a mixture (2 g) of the crude allyl stannanes (1B) and (3B)in the above manner gave the hydroxy ester (2B) (413 mg, 96% from(10B)), δ 7.10 (2 H, d, J 8.5 Hz, 1- and 5-protons), 6.85 (2 H, d, J 8.5Hz, 2- and 4-proton), 5.32 (1 H, ddd, J 16.5, 10, and 8 Hz, 7-proton),4.75 (1 H, dd, J 10 and 2 Hz, cis-6-proton), 4.69 (1 H, dd, J 9 and 7.5Hz, 17-proton), 4.68 (1 H, dd, J 16.5 and 2 Hz, trans-6-proton), 3.94 (1H, m, 11-proton), 3.79 (3 H, s, OCH₃), 2.38-2.13 (4 H, m), 1.54-1.23 (4H, m), 1.20 (9 H, s, OBu^(t)), 1.04 (3 H, s, 18-CH₃), (Found: M⁺386.2462. C₂₄ H₃₄ O₄ requires M 386.2457), and the hydroxy ester (4B)(190 mg, 89% from (11B)), δ 7.09 (2 H, d, J 8.5 Hz, 1- and 5-protons),6.80 (2 H, d, H 8.5 Hz, 2- and 4-protons), 5.09-5.02 (2 H, vinylprotons), 4.88-4.83 (1 H, m, vinyl proton), 4.76 (1 H, dd, J 8.5 and 7Hz, 17-proton), 4.24 (1 H, dt, J 4 and 2 Hz, 11-proton), 3.79 (3 H, s,OCH₃), 3.08 (1 H, d, J 6 Hz, 9-proton), 2.81 (1 H, m, 8-proton),2.19-1.90 (4 H, m), 1.70-1.23 (4 H, m), 1.20 (9 H, s, OBu^(t)), 1.15 (3H, s, 18-CH₃).

11α-Hydroxy-5,6-seco-9α-estra-1,3,5(10),6-tetraene-17β-yltrimethylacetate (2A) and11β-hydroxy-5,6-seco-9β-estra-1,3,5(10),6-tetraene-17β-yltrimethylacetate (4A).

Treatment of a mixture (170 mg, 0.34 mmol, α:β ratio 1.67:1) of theepoxides (10A) and (11A) with tri-n-butyltin hydride in the mannerdescribed previously gave a crude mixture of the epoxy allyl stannanes(1A) and (3A), which was allowed to react with zinc bromide in themanner described above. Chromatography of the crude product on silica (5g) eluted with ether-light petroleum (1:10) gave, first,11β-hydroxy-5,6-seco-9β-estra-1,3,5(10),6-tetraene-17β-yltrimethylacetate (4A), (45 mg, 37%), m.p. 93°-95° C. (from ether-lightpetroleum), ν_(max) 1715 cm⁻¹ (C═O), δ (250 MHz) 7.30-7.13 (5 H, m,aromatic protons), 5.06-4.81 (3 H, m, protons at 6 and 7), 4.76 (1 H,dd, J 9 and 7 Hz, 17-proton), 4.30-4.23 (1 H, m, 11-proton), 3.12 (1 H,d, J 6 Hz, 9-proton), 2.90-2.77 (1 H, m, 8-proton), 1.71 (9 H, s,OBu^(t) ), 1.22 (3 H, s, 18-CH₃), m/z 356 (M⁺), and then11α-Hydroxy-5,6-seco-9α-estra-1,3,5(10),6-tetraene-17β-yltrimethylacetate (2A) (83 mg, 61%), m.p. 103°-105° C. (from ether-lightpetroleum), ν_(max) 1720 cm⁻¹ (C═O), δ 7.34-7.13 (5 H, m, aromaticprotons), 5.31 (1 H, ddd, J 17, 10, and 8 Hz, 7-proton), 4.70-4.61 (3 H,m, 6- and 17-protons), 3.98 (1 H, ddd, J 10, 9, and 4.5 Hz, 11-proton),1.20 (9 H, s, OBu^(t)), 1.02 (3 H, s, 18-CH₃), m/z 254 (M-102).

3-Methoxy-11α-hydroxy-5,6-secoestra-1,3,5(10),6-tetraene-17-one (2C).

Treatment of the mixture (1:1 g) of epoxy keto sulphones (10C) and (11C)in sequence with tri-n-butyltin hydride and zinc bromide in the mannerdescribed above gave, after chromatography on silica, the hydroxy ketone(2C) (125 mg, 33% over two steps) ν_(max) 3500 (OH) and 1740 cm₋₁ (C═O),δ 7.10 (2 H, d, J 8.5 Hz, 1- and 5-protons), 6.87 (2 H, d, J 8.5 Hz, 2-and 4-protons), 5.37 (1 H, ddd, J 16.5, 10, and 8.5 Hz, 7-proton), 4.84(1 H, dd, J 10 and 1.5 Hz, cis-6-proton), 4.76 (1 H, ddd, J 16.5, 1.5,and 0,5 Hz, trans-6-proton), 4.00 (1 H, ddd, J 11.5, 10, and 5 Hz,11-proton), 3.80 (3 H, s, OCH₃), 2.53 (1 H, ddd, J 10, 8.5, and 1 Hz,8-proton), 2.43 (1 H, dt, J 10 and 8.5 Hz, 9-proton), 2.32-1.34 (7 H,m), 1.79 (1 H, br s, OH), 1.08 (3 H, 3 H, s, 18-CH₃), (Found: M⁺300.1733. C₁₉ H₂₄ O₃ requires 300.1725), together with3-methoxy-11β-hydroxy-5,6-seco-9β-estra-1,3,5(10),6-tetraene-17-one (4C)(130 mg) contaminated with unidentified organotin compounds.

3-Methoxy-11α-hydroxy-5,6-seco-9α-estra-1,3,5(10),6-tetraene-17-ethyleneketal (2E) and

3-methoxy-11β-hydroxy-5,6-seco-9β-estra-1,3,5(10),6-tetraene-17-ethyleneketal (4E).

Treatment of the mixture (116 mg) of epoxy keto sulphones (10E) and(11E) in sequence with tri-n-butyltin hydride and zinc bromide in themanner described above gave, after chromatography on silica, the11α-alcohol (2E) (18 mg), (44% over two steps) ν_(max) 3500 cm⁻¹ (OH), δ7.09 (2 H, d, J 8.5 Hz, 1- and 5-protons), 6.85 (2 H, d, J 8.5 Hz, 2-and 4-protons), 5.32 (1 H, ddd, J 16.5, 10, and 8.5 Hz, 7-proton), 4.73(1 H, dd, J 10 and 2 Hz, cis-6-proton), 4.66 (1 H, dd, J 17 and 2 Hz,trans-6-proton), 3.99-3.89 (4 H, m, OCH₂ CH₂ O), 3.79 (3 H, s, OCH₃),2.30-1.20 (11 H, m), 1.05 (3 H, s, 18-CH₃),

(Found: M⁺ 344.1996. C₂₁ H₂₈ O₄ requires 344.1987). The 11b-alcohol (4E)(14 mg), ν_(max) 3500 cm⁻¹ (OH), δ (250 MHz) 7.05 (2 H, J 8 Hz, 1- and5-protons), 6.82 (2 H, d, J 8 Hz, 2-and 4-protons), 5.15-4.90 (3 H, m,vinylic protons), 4.24 (1 H, m, 11-proton), 3.96 (4 H, m, OCH₂ CH₂ O),3.79 (3 H, s, OCH₃), 3.07 (1 H, dd, J 6 and 2 Hz, 9-proton), 2.76 (1 H,ddd, J 10, 8, and 6 Hz, 8-proton), 2.49-1.92 (5 H, m), 1.85-1.10 (3 H,m), 1.05 (3 H, s, 18 -CH₃),

(Found: M+ 344. C₂₁ H₂₈ O₄ requires M 344), was also obtained,contaminated with minor amounts of an unknown organotin compound.

3-Methoxy-5,6-secoestra-1,3,5(10),6-tetraene-11α,17β-diol (12).

A solution of the hydroxy-acetate (2) (291 mg, 0.85 mmol) in dry ether(2 ml) was added dropwise to a stirred solution of lithium aluminiumhydride (32 mg, 0.85 mmol) in dry ether (5 ml) at 0° C. After 1 h theexcess lithium aluminium hydride was destroyed by careful addition ofwet ether, and then water (dropwise), the ethereal solution was decantedoff, dried, and evaporated to give the product (12) (250 mg, 98%),ν_(max) 3400 cm⁻¹ (OH), δ 7.13 (2 H, d, J 8 Hz, 1- and 5-protons), 6.89(2 H, d, J 8 Hz, 2- and 4-protons), 5.33 (1 H, ddd, J 16.5, 10, and 8Hz, 7-proton), 4.76 (1 H, dd, J 10 and 2 Hz, cis 6-proton), 4.70 (1 H,dd, J 16.5 and 2 Hz, trans 6-proton), 4.00 (1 H, ddd, H 11, 9.5, and 5Hz, 11-proton), 3.83 (1 H, t, J 9 Hz, 17-proton), 3.82 (3 H, s, OCH₃),2.40-1.13 (9 H, m), 1.71 (2 H, s, OH), 0.99 (3 H, s, 18-CH₃);

(Found: M⁺ 302. C₁₉ H₂₆ O₃ requires M 302).

3-Methoxy-11α,17β-di(trimethylacetoxy)-5,6-secoestra-1,3,5(10),6-tetraene(13).

Trimethylacetyl chloride (0.34 ml, 2.8 mmol) was added to a stirredsuspension of dry silver cyanide (75 mg, 0.56 mmol) in a solution of thediol (12) (84 mg, 0.28 mmole) in dry benzene (5 ml) at room temperature.Stirring was continued overnight, after which the solution was dilutedwith ether (5 ml), filtered, and the filtrate evpaorated under reducedpressure. Chromatography of the residue on silica (1 g) eluted withether-light petroleum gave the product (13) (120 mg, 92%), m.p. 114°-5°C. (from ether-light petroleum), ν_(max) 1730 cm⁻¹ (CO), δ (250 MHz)7.12 (2 H, d, J 8.5 Hz, 1- and 5-protons), 6.77 (2 H, d, J 8.5 Hz, 2-and 4-protons), 5.33 (1 H, ddd, J 16.5, 10, and 8 Hz, 7-proton), 5.24 (1H, dt, H 11, and 5 Hz, 11-proton) 4.77 (1 H, dd, J 10 and 2 Hz, cis6-proton), 4.70 (1 H, dd, J 9 and 7.5 Hz, 17-proton), 4.69 (1 H, dd, J16.5 and 2 Hz, trans 6-proton), 3.75 (3 H, s, OCH₃), 2.48 (1 H, t, J 11Hz, 9-proton), 2.42-2.18 (2 H, m), 2.12 (1 H, dd, J 12 and 5 Hz,12-proton), 1.67-1.23 (5 H, m), 1.21 (9 H, s, OBu^(t)), 1.09 (1 H, s,18-CH₃), 0.89 (9 H, s, OBu^(t));

(Found: (ammonia chemical ionization) M⁺ 488. C₂₉ H₄₂ O₅ .NH₄ requires M488).

11α,17β-Di(trimethylacetoxy)-5,6-secoestra-1,3,5(10),6-tetraene (13A).

Esterification of the diol (12A) (0.5 g) in the above manner gave thediester (13A) (0.788 g, 97%), m.p. 121°-124° C. (from ether-lightpetroleum), ν_(max) 1724 cm⁻¹ (CO), δ (250 MHz) 7.27-7.06 (5 H, m,aromatic protons), 5.41-5.22 (2 H, m, 7- and 11-proton), 4.77-4.62 (3 H,m, 6-and 17-proton), 2.52 (1 H, t, J 10.5 Hz, 9-proton), 2.45-2.09 (3 H,m), 1.64-1.24 (5 H, m), 1.20 (9 H, s, OBu^(t)), 1.09 (1 H, s, 18-CH₃),0.86 (9 H, s, OBu^(t));

(Found: M⁺ 440.2945. C₂₈ H₄₀ O₄ requires M 440.2924). Esterification ofthe hydroxy ester (2A) (162 mg) with trimethylacetyl chloride in theabove manner also gave the diester (13A) (188 mg, 93%).

3-Methoxy-11α,17β-di(trimethylacetoxy)-5,6-secoestra-1,3,5(10)-triene-6-ol(14).

A solution of monochloroborane-dimethyl sulphide complex (290 mg, 2.6mmole) and the olefin (13) (120 mg, 0.26 mmole) in dry dichloromethane(5 ml) was kept at 0° C. for 3 h, and then treated with ether (5 ml) andaqueous hydrogen peroxide (30%, 1 ml). After stirring overnight, themixture was diluted with water, extracted with ether, and the etherealextract washed with water, dried, and evaporated. Chromatography of theresidue on silica (2 g) eluted with ether-light petroleum (2:5) gave theproduct (14) (104 mg, 84%), ν_(max) 3500 (OH) and 1720 cm⁻¹ (CO), δ (250MHz) 7.09 (2 H, d, J 8 Hz, 1- and 5-protons), 6.80 (2 H, d, J 8 Hz, 2-and 4-protons), 5.17 (1 H, dt, H 11 and 5 Hz, 11-proton) 4.66 (1 H, dd,J 9 and 7.5 Hz, 17-proton), 3.35 (2 H, m, 6-protons), 3.78 (3 H, s,OCH₃), 2.41 (1 H, t, J 11 Hz, 9-proton), 2.32-2.05 (2 H, m), 1.95-1.74(2 H, m), 1.62-1.23 (7 H, m), 1.20 (9 H, s, OBu^(t)), 1.07 (1 H, s,18-CH₃), 0.89 (9 H, s, OBu^(t));

(Found: M⁺ 506 (ammonia chemica ionization). C₂₉ H₄₄ O₆.NH₄ requires506).

11α,17β-Di(trimethylacetoxy)-5,6-secoestra-1,3,5(10)-triene-6-ol (14A).

Treatment of the unsaturated diester (13A) (1.241 g) in the above mannergave the hydroxy diester (14A) (1.062 g, 82%), m.p. 128°-131° C. (fromether-light petroleum), ν_(max) 3600 (OH) and 1720 cm⁻¹ (CO), δ (250MHz) 7.29-7.12 (5 H, m, aromatic protons), 5.20 (1 H, dt, H 11 and 4 Hz,11-proton) 4.65 (1 H, dd, J 9 and 7 Hz, 17-proton), 3.46-3.23 (2 H, m,6-protons), 2.30 (1 H, m), 2.10 (1 H, dd, J 11.5 and 4 Hz, 12-proton),2.00-1.4 (9 H, m), 1.19 (9 H, s, OBu^(t)), 1.07 (1 H, s, 18-CH₃), 0.83(9 H, s, OBu^(t)); M.sup. + (ammonia chemical ionization) 476.

(Found: C, 73.5; H, 9.0. C₂₈ H₄₂ O₅ requires C, 73.3; H, 9.3%)

3-Methoxy-11α,17β-di(trimethylacetoxy)-5,6-secoestra-1,3,5(10)-triene-6-oicacid (15).

Jones reagent (0.2 ml) was added dropwise to a stirred solution of thealcohol (14) (155 mg, 0.3 ml) in dry acetone (3 ml) at 0° C. After 30min at 0° C., propan-2-ol (2 ml) was added and the solvent removed byevaporation under reduced pressure. The residue was partitioned betweenether and dilute hydrochloric acid, and the ether extract was washedwith water, dried, and evaporated. Chromatography of the residue onsilica (2 g) eluted with ether-light petroleum (4:1) gave the product(15) (131 mg, 82%), m.p. 167°-9° C. (from light petroleum), ν_(max) 1720cm⁻¹ (CO), δ (250 MHz) 7.10 (2 H, d, J 8 Hz, 1- and 5-protons), 6.79 (2H, d, J 8 Hz, 2- and 4-protons), 5.23 (1 H, dt, H 11 and 4.5 Hz,11-proton), 4.67 (1 H, dd, J 9 and 6.5 Hz, 17-proton), 3.73 (3 H, s,OCH₃), 2.48 (1 H, t, J 11 Hz, 9-proton), 2.32-2.06 (6 H, m), 1.75-1.45(4 H, m), 1.20 (9 H, s, OBu^(t)), 1.09 (1 H, s, 18-CH₃), 0.86 (9 H, s,OBu^(t));

(Found: C, 69.6; H, 8.2; M⁺ 520 (ammonia chemical ionization). C₂₉ H₄₂O₇ requires C, 69.3; H, 8.4%; C₂₉ H₄₂ O₇.NH₄ requires M 520).

11α,17β-di(trimethylacetoxy)-5,6-secoestra-1,3,5(10)-triene-6-oic acid(15A).

Oxidation of the hydroxy diester (14A) (105 mg) in the above manner gavethe acid (15A) (87 mg, 81%), m.p. 230°-231° C. (from ether-lightpetroleum), ν_(max) 1720 cm⁻¹ (CO), δ 7.32-7.13 (5 H, m, aromaticprotons), 5.26 (1 H, dt, J 10.5 and 4.5 Hz, 11-proton), 4.69 (1 H, dd, J9 and 7 Hz, 17-proton), 2.69 (2 H, ABX system, J 17, 6.5, and 3.5 Hz,7-protons), 2.53 (1 H, t, J 10.5 Hz, 11-proton), 2.4-1.2 (9 H, m), 1.20(9 H, s, OBu^(t)), 1.09 (3 H, s, 18-CH₃), 0.82 (9 H, s, OBu^(t)), M⁺(ammonnia chemical ionization) 490 (M+NH₃ ),

(Found: C, 71.2; H, 8.3. C₂₈ H₄₀ O₆ requires C, 71.2; H, 8.5%).

3-Methoxy-11α,17β-di(trimethylacetoxy)-estra-1,3,5(10)-triene-6-one(16).

A stirred solution of the acid (15) (151 mg, 0.3 mmole) in dry benzene(3 ml) at room temperature under argon was treated with sodium hydride(8 mg, 0.33 mmol, free of mineral oil). After 15 min, oxalyl chloride(0.26 ml, 3 mmol) was added, the solution kept at 40° C. for 1 h, andthe solvent evaporated under reduced pressure. The residue was dissolvedin dry dichloromethane (5 ml) and treated with freshly ground aluminiumchloride (402 mg, 3 mmol). After 30 min at room temperature water (5 ml)was added, and the mixture was extracted with ether (3×15 ml). Theethereal extract was washed in succession with dilute hydrochloric acid,sodium hydroxide, and water, dried, and evaporated to give a residuewhich was chromatographed on silica (2 g). Elution with ether-lightpetroleum (1:5) gave the product (16) (140 mg, 96%), m.p. 183°-4° C.(from light petroleum), ν_(max) 1720 and 1680 cm⁻¹ (CO), δ (250 MHz)7.54 (1 H, t, J 1.5 Hz, 4-proton), 7.02 (2 H, d, J 1.5 Hz, 1- and2-protons), 5.42 (1 H, dt, H 10 and 5.5 Hz, 11-proton), 4.67 (1 H, dd, J8.5 and 7 Hz, 17-proton), 3.84 (3 H, s, OCH₃), 2.82 (1 H, t, J 11 Hz,9-proton), 2.82 (1 H, dd, J 17 and 3.5 Hz, 12-proton), 2.33 (2 H, ABpart of ABX system, J 12 and 5.5 Hz, 7-protons), 2.28 (1 H, m), 2.06 (1H, qt, J 12, 11, 5.5, and 3.5 Hz, 8-proton), 1.80-1.40 (5 H, m), 1.22 (9H, s, OBu^(t)), 1.21 (9 H, s, OBu^(t)), 0.91 (1 H, s, 18-CH₃);

(Found: C, 71.8; H, 8.2; M⁺ 485 C₂₉ H₄₀ O₆ requires C, 71.9; H, 8.3%;(M+1) 485).

11α,17β-Di(trimethylacetoxy)-estra-1,3,5(10)-triene-6-one (16A).

Treatment of the acid (15A) (172 mg) in sequence with oxalyl chlorideand aluminium chloride in the above manner gave the keto diester (16A)(158 mg, 95%), m.p. 186°-187° C. (from ether-light petroleum), ν_(max)1720 (C═O) and 1680 cm⁻¹ (C═O), δ (250 MHz) 8.05 (1 H, dd, J 7.5 and 2Hz, aromatic proton), 7.48 (1 H, dt, J 7.5 and 2 Hz, aromatic proton),7.36 (1 H, dt, J 7.5 and 1 Hz, aromatic proton), 7.11 (1 H, dt, J 7.5and 1 Hz, aromatic proton), 5.47 (1 H, dt, H 10.5 and 5.5 Hz,11-proton), 4.68 (1 H, dd, H 9 and 7 Hz, 17-proton), 2.93-2.80 (2 H, m),2.43- 1.25 (9 H, m), 1.22 (9 H, s, OBu^(t)), 1.21 (9 H, s, OBu^(t)),0.92 (3 H, s, 18-CH₃), M.sup. + (ammonia chemical ionization) 472(M+NH₃), (Found: C, 74.2; H, 8.45. C₂₈ H₃₈ O₅ requires c, 74.0; H,8.4%).

3-Methoxy-11α,17β-dihydroxy-estra-1,3,5(10)-triene-6-one (5).

The keto-diester (16) (30 mg, 0.06 mmole) was added to a degassed 10%solution of potassium hydroxide in methanol-water (19:1) (4 ml), and thesolution was boiled for 3.5 h under nitrogen. The solvent was removed byevaporation under reduced pressure, and the residue was dissolved inether. The residue was washed in succession with dilute hydrochloricacid and water, dried, and evaporated to give a residue which waschromatographed on silica (1 g) eluted with ether to give the product(5) (16 mg, 82%), m.p. 113°-4° C. (from ether-light petroleum), ν_(max)3400 (OH) and 1675 cm⁻¹ (CO), δ (400 MHz) 8.08 (1 H, dd, J 8.5 and 1 Hz,1-proton), 7.54 (1 H, d, J 3 Hz, 4-proton), 7.12 (1 H, dd, H 8.5 and 3Hz, 2-proton), 4.27 (1 H, dt, H 10 and 5 Hz, 11-proton), 3.85 (3 H, s,OCH₃), 3.79 (1 H, t, J 8 Hz, 17-proton), 2.78 (1 H, dd, J 17 and 2,5 Hz,12-proton), 2.45 (1 H, t, J 10 Hz, 9-proton), 2.35 (1 H, A portion ofABX system, J 12 and 5 Hz, 7-proton), 2.35 (1 H, B portion of ABXsystem, J 12 and 5 Hz, 7-proton), 2.18 (2 H, m), 1.96 (1 H, qt, J 14,10, 5, and 3.5 Hz, 8-proton), 1.86 (2 H, br s, OH), 1.56-1.27 (5 H, m),0.8 (3 H, s, 18-CH₃);

(Found: M⁺ 316. C₁₉ H₂₄ O₄ requires M 316).

11α,17β-Dihydroxy-estra-1,3,5(10)-triene-6-one (5A).

Hydrolysis of the keto diester (16A) (158 mg) in the above manner gavethe keto diol (5A) (74 mg, 74%), m.p. 205°-208° C. (from methanol,ν_(max) 3600 (OH) and 1680 cm⁻¹ (C═O), δ (250 MHz) 8.13 (1 H, dd, J 8and 0.5 Hz, aromatic proton), 8.04 (1 H, dd, J 7 and 1,5 Hz, aromaticproton), 7.56 (1 H, dt, J 8 and 1.5 Hz, aromatic proton), 7.36 (1 H, dt,J 7 and 0.5 Hz, aromatic proton), 4.32 (1 H, ddd, J 10.5, 9.5, and 5 Hz,11-proton), 3.79 (1 H, t, J 8 Hz, 17-proton), 2.77 (1 H, dd, J 17 and3.5 Hz, 7-proton), 2.5 (1 H, t, J 10.5 Hz, 9-proton), 2.41-1.22 (11 H,m), 0.79 (3 H, s, 18-CH₃), (Found: M 286.1572. C₁₈ H₂₂ O₃ requires M286.1567).

3-Methoxy-17β-acetoxy-5,6-seco-9β-estra-1,3,5(10),6-tetraene-11-one(17).

Jones reagent (2 ml) was added dropwise to a stirred solution of thecrude 11β-alcohol (4) (2 g) in dry acetone (30 ml) at 0° C. After 30 minpropan-2-ol (10 ml) was added, and the solvent was evaporated underreduced pressure. The residue was treated with dilute hydrochloric acid(20 ml) and extracted with ether (3×30 ml). The combined etherealextracts were washed with water, dried, and evaporated to give a residuewhich was chromatographed on silica (25 g). Elution with ethylacetate-light petroleum (3:10) gave the product (17) (811 mg) as an oil,ν_(max) 1730 and 1710 cm⁻¹ (CO), δ (400 MHz) 7.18 (2 H, d, J 8 Hz, 1-and 5-protons), 6.83 (2 H, d, J 8 Hz, 2- and 4-protons), 5.26 (1 H, ddd,J 16.5, 10, and 9 Hz, 7-proton), 5.03 (1 H, dd, J 16.5 and 2 Hz, trans6-proton), 4.90 (1 H, t, J 9 Hz, 17-proton), 4.89 (1 H, dd, J 10 and 2Hz, cis 6-proton), 3.79 (3 H, s, OCH₃), 3.64 (1 H, d, J 6.5 Hz,9-proton), 2.75-2.67 (1 H, m, 8-proton), 2.60 (2 H, AB system, J 14 Hz,12-protons), 2.38-2.25 (1 H, m, 14-proton), 2.08 (3 H, s, COCH₃),1.74-1.25 (4 H, m), 0.92 (3 H, s, 18-CH₃);

(Found: M⁺ 342. C₂₁ H₂₆ O₄ requires M 342).

3-Methoxy-17β-acetoxy-5,6-secoestra-1,3,5(10),6-tetraene-11-one (18).

(a) A solution of the ketone (17) (800 mg, 2.3 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (355 mg, 2.3 mmol) in drydichloromethane (40 ml) was boiled for 3 h, cooled, washed with dilutehydrochloric acid and water, dried, and evaporated to give the product(18) (791 mg, 99%), m.p. 92 °-93° C., ν_(max) 1740 and 1705 cm⁻¹, δ (400MHz) 6.93 (2 H, d, J 8 Hz, 1- and 5-protons), 6.86 (2 H, d, J 8 Hz, 2-and 4-protons), 5.45 (1 H, ddd, J 16, 10, and 8 Hz, 7-proton), 4.92 (1H, t, J 8 Hz, 17α-proton), 4.84 (1 H, dd, J 10 and 1 Hz, cis 6-proton),4.74 (1 H, dd, J 16 and 1 Hz, trans 6-proton), 3.70 (3 H, s, OCH₃), 3.21(1 H, d, J 11 Hz, 9-proton), 2.53 (2 H, AB system, J 13 Hz, 12-protons),2.56 (1 H, ddd, J 11, 8, and 8 Hz, 8-proton), 2.35-2.25 (1 H, m,16-proton), 2.07 (3 H, s, COCH₃), 2.05-1.97 (1 H, m, 14-proton),1.81-1.40 (3 H, m,), 0.94 (3 H, s, 19-CH₃);

(Found: C, 73.4; H, 7.4; M⁺ 342. C₂₁ H₂₆ O₄ requires C, 73.7; H, 7.6%; M342).

(b) Jones reagent (0.2 ml) was added dropwise to a stirred solution ofthe 11α-alcohol (2) (70 mg) in dry acetone (2 ml) at 0° C. After 30 minpropan-2-ol (1 ml) was added, and the solvent was evaporated underreduced pressure. The residue was treated with dilute hydrochloric acid(2 ml) and extracted with ether (3×10 ml). The combined etherealextracts were washed with water, dried, and evaporated to give a residuewhich was chromatographed on silica (1 g). Elution with ether-lightpetroleum (1:1) gave the product (18) (58 mg, 83%), identical to thesample prepared above.

3-Methoxy-17β-acetoxy-5,6-secoestra-1,3,5(10),6-tetraene-11β-ol (19).

Sodium borohydride (70 mg, 1.85 mmol) was added to a solution of theketo-ester (18) (126 mg, 0.37 mmol) in dry ethanol (5 ml) at 20° C.After 60 min dilute hydrochloric acid was added, the solvent wasevaporated under reduced pressure, and the residue was partitionedbetween ether and water. The ethereal extract was washed with dilutehydrochloric acid and water, dried and evaporated to give a residuewhich was chromatographed on silica (2 g). Elution with ethylacetate-light petroleum (3:10) gave the product (19) (104 mg, 82%) as anoil, ν_(max) 3420 (OH) and 1730 cm⁻¹ (CO), δ (250 MHz) 7.12 (2 H, d, J8.5 Hz, 1- and 5-protons), 6.86 (2 H, d, J 8.5 Hz, 2- and 4-protons),5.32 (1 H, ddd, J 17, 10, and 8.5 Hz, 7-proton), 4.92 (1 H, ddd, J 17,2, and 0.5 Hz, trans 6-proton), 4.85 (1 H, dd, J 10 and 2 Hz,cis-6-proton), 4.68 (1 H, dd, J 9 and 7 Hz, 17-proton), 3.96 (1 H, dt, J3.5 and 2 Hz, 11-proton), 3.28 (3 H, s, OCH₃), 2.75 (1 H, ddd, J 11 and8.5 Hz, 8-proton), 2.59 (1 H, dd, J 11 and 3 Hz, 9-proton), 2.19-2.12 (2H, m, 12-protons), 2.06 (3 H, s, COCH₃), 1.63-1.31 (5 H, m), 1.15 (3 H,s, 18-CH₃);

(Found: M⁺ 344. C₂₁ H₂₈ O₄ requires M 344), and its isomer (2) (18 mg,12%), identical with an authentic sample.

3-Methoxy-11β,17β-diacetoxy-5,6-secoestra-1,3,5(10),6-tetraene (20).

A solution of the hydroxy-ester (19) (50 mg, 0.15 mmol) in dry benzene(2 ml) was treated with dry silver cyanide (39 mg, 0.3 mmol) and acetylchloride (118 mg, 1.5 mmol) at room temperature. After 16 h ether (2 ml)was added, the solution was filtered through Hyflosupercel, and thefiltrate evaporated under reduced pressure. Chromatography of theresidue on silica (1 g) eluted with ethyl acetate-light petroleum (3:10)gave the product (20) (53 mg, 94%), ν_(max) 1740 cm⁻¹ (CO), δ (250 MHz)7.07 (2 H, d, J 8 Hz, 1- and 5-protons), 6.77 (2 H, d, J 8 Hz, 2-and4-protons), 5.30 (1 H, ddd, J 17, 10, and 8 Hz, 7-proton), 5.12 (1 H,dt, J 3.5 and 2 Hz, 11-proton), 4.90 (1 H, dd, J 17 and 2 Hz, trans6-proton), 4.85 (1 H, dd, J 10 and 2 Hz, cis-6-proton), 4.67 (1 H, dd, J9 and 6.5 Hz, 17-proton), 3.76 (3 H, s, OCH₃), 2.74 (1 H, m), 2.60 (1 H,dd, J 11 and 3.5 Hz, 9-proton), 2.18-2.06 (2 H, m) 2.04 (3 H, s, COCH₃),1.86 (3 H, s, COCH₃), 1.71-1.34 (5 H, m), 1.07 (3 H, s, 18-CH₃);

(Found: M⁺ 386. C₂₃ H₃₀ O₅ requires M 386).

3-Methoxy-11β,17β-diacetoxy-5,6-secoestra-1,3,5(10)-triene-6-ol (21).

A solution of monochloroborane-dimethyl sulphide complex (781 mg, 7mmole) and the olefin (20) (272 mg, 0.7 mmole) in dry dichloromethane (8ml) was kept at 0° C. for 2.5 h, and then treated with ether (8 ml),water (10 ml) and aqueous hydrogen peroxide (30%, 3 ml). After stirringfor 2 h at 20° C., the mixture was extracted with ether, and the extractwas washed with water, dried, and evaporated. Chromatography of theresidue on silica (4 g) eluted with ethyl acetate-light petroleum (2:5)gave the product (21) (242 mg, 85%), ν_(max) 3420 (OH) and 1730 cm⁻¹(CO), δ (250 MHz) 7.12 (2 H, d, J 8 Hz, 1- and 5-protons), 6.80 (2 H, d,J 8 Hz, 2- and 4-protons), 5.05 (1 H, dt, J 3 and 2.5 Hz, 11-proton),4.63 (1 H, dd, J 9 and 6.5 Hz, 17-proton), 3.78 (3 H, s, OCH₃), 3.47 (2H, ddt, J 15, 13, 10, and 6 Hz, 6-protons), 2.53 (1 H, dd, J 12 and 3Hz, 9-proton), 2.32-2.15 (2 H, m), 2.11 (1 H, dd, J 14.5 and 2.5 Hz,12-proton), 2.04 (3 H, s, COCH₃), 1.88 (3 H, s, COCH₃), 1.83-1.37 (7 H,m), 1.04 (3 H, s, 18-CH₃); (Found: M⁺ 404. C₂₃ H₃₂ O₆ requires M 404),and its 7-hydroxy regioisomer 6%).

3-Methoxy-11β,17β-diacetoxy-5,6-secoestra-1,3,5(10)-triene-6-oic acid(22).

Jones reagent (1 ml) was added dropwise to a stirred solution of thealcohol (21) (120 mg, 0.3 mmole) in dry acetone (5 ml) at 0° C. After 30min at 0° C., propan-2-ol (2 ml) was added and the solvent removed byevaporation under reduced pressure. The residue was partitioned betweenether and dilute hydrochloric acid, and the ether extract was washedwith water, dried, and evaporated. Chromatography of the residue onsilica (2 g) eluted with ether-light petroleum (1:1) gave the product(22) (101 mg, 81%), ν_(max) 1730 and 1710 cm⁻¹ (CO), δ (250 MHz) 7.13 (2H, d, J 8.5 Hz, 1- and 5-protons), 6.80 (2 H, d, J 8.5 Hz, 2- and4-protons), 5.10 (1 H, dt, J 3 and 2.5 Hz, 11-proton), 4.65 (1 H, dd, J9 and 6.5 Hz, 17-proton), 3.77 (3 H, s, OCH₃), 2.70-2.60 (1 H, m), 2.59(1 H, dd, J 11 and 3 Hz, 9-proton), 2.32-2.09 (3 H, m), 2.04 (3 H, s,COCH₃), 1.90 (3 H, s, COCH₃), 1.80-1.50 (6 H, m), 1.08 (3 H, s, 18-CH₃);(Found: M⁺ 418. C₂₃ H₃₀ O₇ requires M 418).

3-Methoxy-11β,17β-diacetoxy-estra-1,3,5(10)-triene-6-one (23).

A stirred solution of the acid (22) (44 mg, 0.105 mmole) in dry benzene(5 ml) at room temperature under argon was treated with sodium hydride(2.5 mg, 0.105 mmol, free of mineral oil). After 10 min, oxalyl chloride(0.1 ml, 1.15 mmole) was added, the solution kept at 40° C. for 1 h, andthe solvent evaporated under reduced pressure. The residue was dissolvedin dry dichloromethane (5 ml) and treated with freshly ground aluminiumchloride (141 mg, 1.05 mmol). After 30 min at room temperature water (5ml) was added, and the mixture was extracted with ether (3×10 ml). Theethereal extract was washed in succession with dilute hydrochloric acidand water, dried, and evaporated to give a residue which waschromatographed on silica (1 g). Elution with ether-light petroleum(3:10) gave the product (23) (42 mg, 99%), m.p. 199°-200° C. (fromether-light petroleum), ν.sub. max 1720 and 1675 cm⁻¹ (CO), δ (250 MHz)7.57 (1 H, t, J 2 Hz, 4-proton), 7.07 (2 H, d, 1- and 2-protons), 5.84(1 H, dt, J 3 and 2 Hz, 11-proton), 4.69 (1 H, dd, J 9 and 7 Hz,17-proton), 3.83 (3 H, s, OCH₃), 2.81 (1 H, dd, J 14.5 and 3 Hz,12-proton), 2.80 (1 H, dd, J 11 and 3 Hz, 9-proton), 2.23 (2 H, m), 2.22(2 H, AB part of ABX system, J 11.5 and 2.5 Hz, 7-protons), 2.04 (3 H,s, COCH₃), 1.88 (3 H, s, COCH₃), 1.82-1.42 (5 H, m), 0.96 (3 H, s,18-CH₃);

(Found: M⁺ 400. C₂₃ H₂₈ O₆ requires M 400).

3-Methoxy-11β,17β-dihydroxy-estra-1,3,5(10)-triene-6-one (6A).

The keto-diester (23) (21 mg, 0.05 mmole) was added to a degassed 10%solution of potassium hydroxide in methanol-water (19:1) (4 ml), and thesolution was boiled for 15 min under nitrogen. The solvent was removedby evaporation under reduced pressure, and the residue was dissolved inether. The extract was washed in succession with dilute hydrochloricacid and water, dried, and evaporated to give a residue which waschromatographed on silica (1 g) eluted with ether to give the product(6A) (15 mg, 90%), m.p. 225°-6° C. (from ether-light petroleum), ν_(max)3460 (OH) and 1655 cm⁻¹ (CO), δ (250 MHz) 7.61 (1 H, d, J 2.5 Hz,4-proton), 7.37 (1 H, d, J 8 Hz, 1-proton), 7.17 (1 H, dd, J 8 and 2.5Hz, 2-proton), 4.84 (1 H, dt, H 3 and 2.5 Hz, 11-proton), 3.85 (3 H, s,OCH₃), 3.74 (1 H, dd, J 9 and 7 Hz, 17-proton) 2.78 (1 H, dd, J 15 and2.5 Hz, 12-proton), 2.71 (1 H, dd, J 10.5 and 2.5 Hz, 9-proton), 2.44(10 H, m), 1.04 (3 H, s, 18-CH₃);

(Found: M⁺ 316. C₁₉ H₂₄ O₄ requires M 316).

6-Chloro-3-methoxy-11β,17β-dihydroxy-estra-1,3,5(10)-triene (24).

A solution of triphenyl phosphine (107 mg, 0.41 mmol) and the alcohol(21) (110 mg, 0.27 mmol) in dry carbon tetrachloride (5 ml) was refluxedfor 16 h under nitrogen, then cooled, and the solvent evaporated underreduced pressure. The residue was chromatographed on silica (2 g) elutedwith ether-light petroleum (3:10) to give the product (24) (72 mg, 62%),m.p. 150°-1° C., ν_(max) 1730 cm⁻¹ (CO), δ (250 MHz) 7.11 (2 H, d, J 8.5Hz, 1- and 5-protons), 6.81 (2 H, d, J 8.5 Hz, 2- and 4-protons), 5.05(1 H, dt, J 3.5 and 2 Hz, 11-proton), 4.64 (1 H, dd, J 9 and 6.5 Hz,17-proton), 3.79 (3 H, s, OCH₃), 3.30 (2 H, dt, J 8 and 2.5 Hz,6-protons), 2.48 (1 H, dd, J 11.5 and 3.5 Hz, 9-proton), 2.36-2.16 (2 H,m), 2.11 (1 H, dd, J 14.5 and 2.5 Hz, 12-proton), 2.05 (3 H, s, COCH₃),1.90 (3 H, s, COCH₃), 1.85-1.30 (7 H, m), 1.05 (3 H, s, 18-CH₃).

11β,17β-Diacetoxy-3-methoxy-estra-1,3,5(10)-triene (25).

Freshly ground aluminium chloride (171 mg, 1.3 mmol) was added to astirred solution of the chloride (24) (54 mg, 0.13 mmol) in drydichloromethane (5 ml). After 30 min water (5 ml) was added, and themixture was extracted with ether (3×15 ml). The extract was washed insuccession with dilute hydrochloric acid and water, dried, andevaporated. The residue was chromatographed on silica (1.5 g) elutedwith ether-light petroleum (3:10) to give the product (25) (50 mg, 99%),m.p. 214°-215° C., ν_(max) 1730 cm⁻¹ (CO), δ (400 MHz) 6.96 (1 H, d, J 8Hz, 1-proton), 6.66 (1 H, dd, J 8 and 2.5 Hz, 2-proton), 6.63 (1 H, d, J2.5 Hz, 4-proton), 5.78 (1 H, dt, J 3 and 2.5 Hz, 11-proton), 4.66 (1 H,dd, J 8.5 and 6.5 Hz, 17-proton), 3.78 (3 H, s, OCH₃), 2.95-2.79 (2 H,m), 2.50 (1 H, dd, J 10 and 3 Hz, 9-proton), 2.31-2.14 (1 H, m), 2.21 (1H, dd, J 14.5 and 2.5 Hz, 12-proton), 2.04 (3 H, s, COCH₃), 2.00-1.8 (2H, m), 1.87 (3 H, s, COCH₃), 1.78 (1 H, m), 1.63-1.29 (5 H, m), 0.95 (3H, s, 18-CH₃);

(Found: M⁺ 336. C₂₃ H₃₀ O₅ requires M 336).

11β,17β-Dihydroxy-3-methoxy-estra-1,3,5(10)-triene (6).

A solution of the diacetate (25) (25 mg, 0.065 mmol) in dry ether (1 ml)was added to a stirred solution of lithium aluminium hydride (5 mg, 0.13mmol) in dry ether (2 ml) at 0° C. under argon. After 15 min, excesslithium aluminium hydride was destroyed by addition of wet ether andthen dropwise addition of water. The ethereal layer was separated,dried, and evaporated, and the residue was chromatographed on silica (1g) to give the product (6) (18 mg, 91%), m.p. 161°-2° C. (fromether-light petroleum), ν_(max) 3420 cm⁻¹ (OH), δ (250 MHz), 7.21 (1 H,d, J 8 Hz, 1-proton), 6.76 (1 H, dd, J 8 and 2.5 Hz, 2-proton), 6.67 (1H, d, J 2.5 Hz, 4-proton), 4.74 (1 H, m, 11-proton), 3.78 (3 H, s,OCH₃), 3.71 (1 H, m, 17-proton), 2.86 (2 H, m, 7-protons), 2.44 (1 H,dd, J 11 and 2 Hz, 9-proton), 2.28 (1 H, dd, J 14 and 2.5 Hz,12-proton), 2.11 (1 H, qt, J 11, 9, 2.5, and 2 Hz, 8-proton), 1.98-1.31(7 H, m), 1.61 (2 H, br s OH), 1.03 (3 H, s, 18-CH₃);

(Found: M⁺ 302. C₁₉ H₂₆ O₃ requires M 302).

3-Methoxy-11α,17β-di(trimethylacetoxy)-estra-1,3,5(10)-triene (26).

Methanesulphonyl chloride (5.4 mg, 0.047 mmol) was added to a stirredsolution of the hydroxy diester (14) (21 mg, 0.043 mmol) andtriethylamine (7 mg) in dichloromethane (1 ml) at 0° C. After 10 min thesolvent was removed by evaporation under reduced pressure to give thecrude methanesulphonate, which was dissolved in dry dichloromethane (2ml) and treated with aluminium trichloride (54 mg, 0.43 mmol). After 30min at room temperature, water (2 ml) was added, and the mixture wasextracted with ether (3×10 ml). The extract was washed with dilutehydrochloric acid and water, dried, evaporated to give a residue whichwas chromatographed on silica (1 g) eluted with ether-light petroleum(1:9) to give the product (26) (18 mg, 89%), ν_(max) 1730 cm⁻¹ (C═O), δ(250 MHz) 6.92 (1 H, d, J 8 Hz, 1-proton), 6.64 (2 H, m, aromaticprotons), 5.38 (1 H, dt, J 10 and 5 Hz, 11-proton), 4.65 (1 H, dd, J 8.5and 7 Hz, 17-proton), 3.76 (3 H, s, OCH₃), 2.83 (2 H, m, 6-protons),2.49 (1 H, t, J 10 Hz, 9-proton), 2.28 (1 H, A part of ABX system, J 12and 5 Hz, 12-proton), 1.97-1.31 (8 H, m), 1.20 (18 H, s, two OBu^(t)),0.89 (3 H, s, 18-CH₃),

(Found: (ammonia chemical ionization) M⁺ 488. C₂₉ H₄₂ O₅.NH₄ requires M488).

11α,17β-Di(trimethylacetoxy)-estra-1,3,5(10)-triene (26A).

Treatment of the hydroxy diester (14A) (343 mg) in sequence withmethanesulphonyl chloride and aluminium chloride in the above mannergave the diester (26A) (301 mg, 91%), m.p. 121°-123° C. (fromether-light petroleum), ν_(max) 1725 cm⁻¹ (C═O), δ 7.14-7.07 (3 H, m,aromatic protons), 7.03-6.96 (1 H, m, 1-proton), 5.44 (1 H, dt, J 10.5and 5 Hz, 11-proton), 4.65 (1 H, dd, J 8.5 and 7 Hz, 17-proton), 2.84 (2H, dd, J 8 and 7 Hz, 6-protons), 2.54 (1 H, t, J 10.5 Hz, 9-proton),1.21 (9 H, s, OBu^(t)), 1.19 (9 H, s, OBu^(t)), 0.89 (3 H, s, 18-CH₃),M⁺ (ammonia chemical ionization) 458 (M+NH).

3-Methoxy-estra-1,3,5(10)-11α,17β-diol (6B).

A solution of the methoxy diester (26) (18 mg, 0.04 mmol) in dry ether(0.5 ml) was added to a solution of lithium aluminium hydride (1.56 mg,0.04 mmol) in ether (1 ml) at 0° C. After 30 min wet ether was addedcarefully, followed by water dropwise. The ether solution was decantedoff, dried, and evaporated to give the product (6B) (11 mg, 91%), m.p.156°-7° C. (from ether-light petroleum), ν_(max) 3500 cm⁻¹ (OH), δ (250MHz) 7.86 (1 H, dd, J 8 and 1 Hz, 1-proton), 6.73 (1 H, dd, J 8 and 3Hz, 2-proton), 6.65 (1 H, d, J 3 Hz, 4-proton), 4.21 (1 H, ddd, J 10.5,9, and 5 Hz, 11-proton), 3.78 (3 H, s, OCH₃), 3.76 (1 H, dd, J 9 and 8Hz, 17-proton), 2.82 (2 H, t, J 6.5 Hz, 6-proton), 2.29 (1 H, dd, J 12and 5 Hz, 12-proton), 2.21-1.20 (10 H, m), 1.66 (2 H, br s, OH), 0.81 (3H, s, 18-CH₃),

(Found: M⁺ 302.1877. C₁₉ H₂₆ O₃ requires M 302.1882).

1,3,5(10)-Estratriene-11α,17β-diol (6C).

Reduction of the diester (26A) with lithium aluminium hydride in theabove manner gave the diol (6C) (90%), m.p. 222°-223° C. (from methanol,ν_(max) 3550 cm⁻¹ (OH), δ (MeOH) 7.88-7.82 (1 H, m, 1-proton), 7.12-6.99(3 H, m, aromatic protons), 4.17 (1 H, ddd, J 10.5, 9.5, and 5 Hz,11-proton), 3.68 (1 H, dd, J 8.5 and 8 Hz, 17-proton), 2.80 (2 H, t, J 7Hz, 6-proton), 2.26 (1 H, dd, J 12 and 5 Hz, 12-proton), 2.16 (1 H, t, J9.5 Hz, 9-proton), 2.10-1.98 (2 H, m, 16-protons), 1.9-0.8 (9 H, m),0.74 (3 H, s, 18-CH₃)

(Found: C, 79.1; H, 8.6; M⁺ 272.1780. C₁₈ H₂₄ O₂ requires C 79.4; H,8.9%; M 272.1776).

2-Acetyl-11α, 17β-di(trimethylacetoxy)-estra-1,3,5(10)-triene (27).

A solution of the diester (26A) (42 mg, 0.095 mmol) and acetyl chloride(0.1 ml, 0.11 g, 1.41 mmol) in dry dichloromethane (1 ml) was treatedwith anhydrous aluminium chloride (63 mg, 0.47 mmol) at roomtemperature. After being stirred to 30 min, a saturated aqueous solutionof sodium bicarbonate was added, and the mixture was extracted withdichloromethane and worked up in the usual manner to give an oil whichwas chromatographed on silica (2 g). Elution with ether-light petroleum(1:5) gave the product (27) (43 mg, 93%), as an oil, ν_(max) 1730 and1685 cm⁻¹ (C═O), δ (250 MHz) 7.75 (1 H, dd, J 8 and 1.5 Hz, 3-proton),7.64 (1 H, d, J 1.5 Hz, 1-proton), 7.20 (1 H, d, J 8 Hz, 4-proton), 5.52(1 H, dt, J 10.5 and 5.5 Hz, 11-proton), 4.66 (1 H, dd, J 9 and 7 Hz,17-proton), 2.89 (2 H, t, J 7 Hz, 6-protons), 2.53 (3 H, s, CH₃ CO),2.37-1.25 (11 H, m), 1.23 (18 H, two s, OBu^(t)), 0.89 (3 H, s, 18-CH₃),M+ (ammonia chemical iionization) 500 (M+NH₃).

2-Acetoxy-11α,17β-di(trimethylacetoxy)-estra-1,3,5(10)-triene (28).

A solution of the ketone (27) (40 mg. 0.83 mmol) and m-chloroperbenzoicacid (43 mg, 0.248 mmol) in dichloromethane (1 ml) was stirred for fourdays at room temperature in the dark. Addition of saturated sodiumbicarbonate solution was followed by the usual working up procedure withmethylene chloride to give a residue which was chromatographed on silica(2 g). Elution with ether-light petroleum (1:20) gave the product (28)(39 mg, 94%), m.p. 143°-146° C. (from ether-light petroleum), ν_(max)1720 cm⁻¹ (C═O), δ (250 MHz) 7.10 (1 H, d, J 8 Hz, 4-proton), 6.86 (1 H,dd, J 8 and 2.5 Hz, 3-proton), 6.71 (1 H, d, J 2.5 Hz, 1-proton), 5.35(1 H, dt, J 10.5 and 5 Hz, 11-proton), 4.65 (1 H, dd, J 8.5 and 7.5 Hz,17-proton), 2.82 (2 H, t, J 7 Hz, 6-proton), 2.54 (1 H, t, J 10.5 Hz,9-proton), 2.24 (3 H, s, CH₃ CO), 1.21 (9 H, s, OBu^(t)), 1.19 (9 H, s,OBu^(t)), 0.89 (3 H, s, 18-CH₃), M⁺ (ammonia chemical ionization) 516(M+NH₃).

Estra-1,3,5(10)-triene-2,11α,17β-triol (6D).

A solution of the triester (28) (150 mg, 0.30 mmol) in dry ether (3 ml)was treated with lithium aluminium hydride (46 mg, 1.41 mmol) at roomtemperature. After 5 min ethyl acetate (1 ml) and then dilutehydrochloric acid (1 ml) was added, and the mixture was worked up withether in the usual manner. Chromatography of the crude product on silica(2 g) eluted with ethyl acetate gave the product (6D) (79 mg, 91%), m.p.229°-232° C. (from acetone), ν_(max) (KBr disc) 3500 cm⁻¹ (OH), δ (MeOH)(250 MHz) 7.41 (1 H, dd, J 2.5 and 1 Hz, 1-proton), 7.39 (1 H, d, J 8Hz, 4-proton), 6.86 (1 H, ddd, J 8, 2.5, and 1 Hz, 3-proton), 4.11 (1 H,dt, J 10.5 and 5 Hz, 11-proton), 3.67 (1 H, t, J 8.5 Hz, 17-proton),3.68 (2 H, t, J 9 Hz, 6-protons), 2.21 (1 H, A part of ABX system,J_(AX) ═5 Hz, J_(AX) ═12 Hz), 2.20-1.20 (13 H, m), 0.74 (3 H, s,18-CH₃),

(Found: M⁺ 288.1719. C₁₈ H₂₄ O₃ requires M 288.1725). ##STR58##

I claim:
 1. A compound having the formulawhere X represents ═O,##STR59## or beta orientated ##STR60## Y represents ═O, ##STR61## betaorientated ##STR62## or beta orientated OH, Z represents alkoxy and R'represents alkyl.